Pseudomonas aeruginosa Infections: Comparison
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Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Sasha H. Shafikhani.

Pseudomonas aeruginosa is an important Gram-negative opportunistic pathogen which causes many severe acute and chronic infections with high morbidity, and mortality rates as high as 40%. What makes P. aeruginosa a particularly challenging pathogen is its high intrinsic and acquired resistance to many of the available antibiotics. 

  • Pseudomonas aeruginosa
  • infection
  • acute infections

1. Acute and Chronic Pneumonia Infection Models

Animal models have been extremely useful in advancing ourthe understanding of P. aeruginosa pathogenesis and for the development and the therapeutic assessment of new antibiotics or novel biologicals to control this pathogen. Although most studies involving P. aeruginosa infections rely on mouse or rat models due to the cost and availability of reagents, larger animal modeling is also performed usually to fulfill the requirement by organizations—such as Food and Drug Administration (FDA)—to evaluate the efficacy and the safety profiles of new investigative biologics in two animal models that approximate human responses with respect to the condition under investigation [154][1]. As was discussed above, P. aeruginosa is an important bacterial pathogen in acute and chronic pneumonia, including the ventilated-associated pneumonia (VAP) and hospital acquired pneumonia (HAP). The first animal model of chronic pulmonary infection was a rat model in which P. aeruginosa infection was initiated by intratracheal inoculation of P. aeruginosa bacteria enmeshed in agar beads [155][2]. In this chronic model of infection, P. aeruginosa was detected during the 35 days of observation. Importantly, infected lungs in these rats exhibited lesions resembling those seen in lung tissues of humans with acute or chronic P. aeruginosa pneumonia, including the presence of goblet-cell hyperplasia, focal areas of necrosis, and acute and chronic inflammatory infiltrate [155][2]. Since then, various similar animal models (in mouse, rat, rabbit, porcine, dog, cat, etc.) of P. aeruginosa infections for acute and chronic pneumonia (including VAP and HAP) have also been described, albeit with modifications in the P. aeruginosa strain, initial inoculum levels, and in the rout of P. aeruginosa delivery into animal [156,157,158,159,160,161][3][4][5][6][7][8].

2. Urinary Tract and Kidney Infection Models

P. aeruginosa also causes urinary tract and kidney infections as discussed above. The initial animal models to assess UTI caused by P. aeruginosa involved intravenous injection of P. aeruginosa into mice [162,163][9][10]. In these systemic infection models, large doses (close to lethal doses) of P. aeruginosa—were needed to establish infection in the urinary tract and kidney. However, the high rate of mortality, due to systemic infection, made these murine models impractical [162,163][9][10]. To overcome this difficulty, artificial manipulations, (e.g., administration of bromoethylamine hydrobromide or ferric sorbitol citrate), were used to make kidneys in animals more susceptible to P. aeruginosa colonization and growth [164,165][11][12]. However, these artificial means made the interpretation of the data unreliable [166][13]. These limitations then led to the development of methods (e.g., surgical implantation of glass beads laden with P. aeruginosa, or transvesical ureteral catheterization) to directly deliver P. aeruginosa into the rat kidney in order to cause infection in this organ [167,168,169][14][15][16]. At present, urinary tract and kidney infection models frequently instill bacteria into the bladder using a catheter, based on the UTI protocol that was developed for Uropathogenic Escherichia coli (UPEC) by Hung et al. [170,171][17][18].

3. Blood Stream and Systemic Infection Models

Different approaches have been used to cause blood and systemic infection in animals with P. aeruginosa. For example, intravenous (i.v.), intraperitoneal (i.p.), or tail vein injections have been used as technical means to cause systemic infection with P. aeruginosa [172,173,174][19][20][21]. P. aeruginosa has also been delivered retro-orbitally to cause systemic infection and sepsis [175][22]. P. aeruginosa systemic infection has been shown to increase pro-inflammatory cytokines both in the blood and tissues, leading to other morbidities such as septic arthritis and gallbladder damage [172,176,177][19][23][24].

4. Keratitis and Corneal Ulcers Infection Models

As this was discussed above, keratitis and corneal ulcer infections are relatively rare but they are very serious medical conditions requiring urgent medical care because of the possibility that they can lead to vision loss in the affected eye(s). In the murine models for corneal ulcer, 2–3 parallel scratches (~1 mm) are usually made by sterile 25-gauge needle on the cornea of anesthetized animal prior to bacterial inoculation [178,179,180,181][25][26][27][28]. Animal models have been informative in showing the potency of antimicrobial activities in human tear [178][25]; in establishing the crucial roles for IL-16 pro-inflammatory cytokine and cathelicidin antimicrobial peptide in corneal defenses against P. aeruginosa [179,180][26][27]; and in demonstrating the therapeutic potential of the broad host range bacteriophage KPP12 in P. aeruginosa clearance and corneal healing [181][28].

5. Endocarditis Infection Models

Animal models of S. aureus infective endocarditis (IE) [182,183][29][30], are commonly used to investigate the underlying pathogenesis, disease progression, potential diagnostic approaches, and therapeutic treatment for endocarditis caused by P. aeruginosa [184][31]; Rabbits [185,186][32][33]. These models are based on surgical valve trauma followed by intravenous injection of bacteria within 10–24 h following the surgical valve trauma. In a rabbit model of endocarditis, with sterile right ventricular cardiac vegetations, Archer et al. demonstrated 78% mortality within 3 weeks, following P. aeruginosa infection [185][32]. In a follow-up study, the same group demonstrated that 14-day treatment with high dose gentamycin (7.5 mg/kg) and carbenicillin (400 mg/kg) was significantly more effective than either therapy alone, resulting in 64% sterilization of cardiac vegetations in this rabbit model of P. aeruginosa endocarditis [186][33]. In a rat model of P. aeruginosa endocarditis, Oechslin et al. demonstrated that a combination of systemic vancomycin and phage therapy was highly effective against P. aeruginosa endocarditis [184][31].

6. Wound and Surgical Site Infection Models

Skin is a formidable barrier against invading pathogens, including P. aeruginosa [187][34]. As an opportunistic pathogen, P. aeruginosa cannot colonize or cause infection in the skin of normal animal unless this barrier is breached by injury [4,5,6,10][35][36][37][38]. Therefore, animal wound and surgical site models of infections for P. aeruginosa (and other pathogens) usually involve full or partial thickness excisional wounding, or addition of bacteria directly to implants or stents before or after their insertion into animals [7,9,188,189,190,191,192,193,194,195][39][40][41][42][43][44][45][46][47][48]. In the settings of injury, P. aeruginosa can efficiently colonize and cause infection [11,12,13,14,196][49][50][51][52][53]. In a recent study, P. aeruginosa was shown to thrive in wound environment, (in a mouse model of wound infection), by dampening the host innate immune responses in wound tissue via inhibition of the NLRC4 inflammasome mediated by its most conserved virulence factor, ExoT [7][39].
Chronic wounds are particularly vulnerable to P. aeruginosa infection [100,197,198][54][55][56]. In a recent study involving db/db type 2 diabetic mouse, it was shown that impairment in the formyl peptide chemokine receptors (FPR) in diabetic neutrophils results in a delay in neutrophil response, rendering diabetic wounds vulnerable to colonization and infection by P. aeruginosa [8][57]. Macrophage response has also been shown to be delayed in db/db diabetic wounds, due to dysregulation in IL-10 expression and signaling [199[58][59],200], further dampening innate immune responses and diabetic wound’s ability to prevent P. aeruginosa infection [9][40]. In other studies, P. aeruginosa has been demonstrated to several other virulence factors (e.g., biofilm, type 3 secretion system (T3SS), pyocyanin, extracellular proteases, and Exotoxin A) to prevent wound healing and exacerbate tissue damage [99,103,104,105,106,201,202][60][61][62][63][64][65][66]. In a burn wound model of infection, P. aeruginosa infection was shown to lead to bacteremia in a manner that was dependent on superoxide response regulator (soxR) expression and function in P. aeruginosa [203][67]. In another report, quorum sensing (QS) was shown to be involved in biofilm maturation and P. aeruginosa colonization and pathogenesis a pressure ulcer infection model in rat [204][68].

7. Immunocompromised Infection Models

As was discussed above, immunocompromised people are highly vulnerable to infection with P. aeruginosa. Not surprisingly, animal models have been developed to assess the impact of P. aeruginosa infection in immunocompromised hosts. For example, Takase et al. demonstrated that P. aeruginosa infection in the calf muscle of immunocompromised mice, (generated by cyclophosphamide), caused high mortality in these mice, in a manner that was mediated by pyoverdine and pyochelin siderophore production in P. aeruginosa [205][69]. In another study, P. aeruginosa was shown to induce death within 46 to 59 h in a leukopenic immunosuppressed mouse model [206][70]. Similarly, Mahmoud et al. demonstrated that wounds in the neutropenic immunocompromised C57BL/6 mice are vulnerable to P. aeruginosa enhanced infection [188][41]. In another study, P. aeruginosa infection was proved to be highly lethal in an immunosuppressed guinea pig model of pneumonia [207][71].

8. Cystic Fibrosis Infection Animal Models

Cystic Fibrosis (CF) is a genetic disorder caused by null mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes for the chloride channel [208,209,210][72][73][74]. Not surprisingly, different transgenic animal species, (i.e., mice, rats, rabbits, ferrets, pigs, and sheep), harboring similar mutations in the CFTR gene have been constructed to model various CF pathologies [211,212,213,214,215,216][75][76][77][78][79][80]. In one report, endobronchial infection with a mucoid P. aeruginosa strain was shown to elicit production of TNF-α, MIP-2, and KC/N51 inflammatory cytokines in bronchoalveolar lavage fluid and cause 80% mortality in CF mice (harboring the S489X mutation of the CFTR gene), thus phenocopying some of the CF hallmark pathologies observed in human [217][81]. Corroborating these studies, van Heeckeren et. al., demonstrated that infection with P. aeruginosa resulted in significantly higher mortality rates, weight loss, higher lung pathology scores, and higher inflammatory mediator and neutrophil levels in the lungs of CF mice as compared to wildtype littermates [218][82]. However, murine models do not completely develop human CF disease severity in the pancreas, lung, intestine, liver, and other organs [219,220][83][84], thus necessitating the need for the development of larger animal models for CF, such as newborn pigs and ferrets [214,215,216,219,221][78][79][80][83][85]. For example, CF pigs were demonstrated to develop airway inflammation, mucus accumulation, and impaired bacterial clearance [222][86]. CF pig lungs contained multiple bacterial species, suggesting impaired immune defenses against bacteria [222][86].

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